Sickle cell disease (SCD) is an autosomal recessive disorder and the most common genetic disease affecting African-Americans. Approximately 0.15% of African-Americans are homozygous for sickle cell disease, and 8% have sickle cell trait. Acute pain crisis, acute chest syndrome (ACS), and pulmonary hypertension are common complications of sickle cell anemia. Pulmonary hypertension (PH) has now been identified as a marker of mortality in adults with sickle cell disease. Sildenafil has been proven beneficial in pulmonary hypertension (PH) and recent phase I/II studies from the intramural National Institutes of Health (NIH) suggest it is well tolerated and efficacious in the SCD population. Furthermore, a number of recent studies have suggested that nitric oxide (NO) based therapies may have a favorable impact on sickle red cells at the molecular level and could improve the abnormal microvascular perfusion that is characteristic of sickle cell anemia. The project had 3 distinct components: 1. Screening Phase. Approximately 1000 subjects with sickle cell disease were to be screened. Assessments included historical and laboratory data, Doppler echocardiogram, 6-minute walk test, plasma/serum, and DNA for banking. 2. Main Interventional Trial. The randomized, double-blind, placebo controlled phase was designed to determine the effects of 16 weeks of sildenafil therapy on exercise endurance, cardiopulmonary hemodynamic parameters and symptoms in this patient population. The open-label follow-up phase was designed to provide up to an additional year of sildenafil therapy to subjects who completed the randomized, double-blind phase. 3. Observational Follow-up Study. Screened patients who did not qualify for participation in the main interventional trial agreed to be contacted every 6-12 months for up to 3 years to assess major disease-related complications, including mortality. Up to 1000 subjects were to be screened based on medical history, physical examination, laboratory testing, transthoracic Doppler-echocardiography, and 6MW test. All consented subjects in this cohort provided plasma and serum for storage and measurement of BNP and DNA for a repository, and continue to be followed prospectively in the Observational Follow-up Study (OFS). Patients found to have a screening TRV of greater than 2.7 m/s were invited to participate in the Main Interventional Trial (MIT). Upon repeat echocardiogram at baseline, patients with TRVs greater than 2.7 m/s who met all inclusion/exclusion criteria were enrolled in the 16 week, randomized, double-blind, placebo-controlled trial of sildenafil versus placebo: the Main Interventional Trial (MIT). The study was to randomize 132 subjects in MIT. Subjects were stratified and randomized based on TRVs. One-half of the subjects, those with TRV greater than or equal to 3.0 m/s, were also to be evaluated with right heart catheterization (RHC) before and after 16 weeks of the intervention. Study assessments were to occur at weeks 6, 10, and 16 or upon early withdrawal. The primary endpoint was change in 6MW distance across for this study phase. Secondary endpoints included non-invasive estimation of pulmonary artery systolic pressure by transthoracic Doppler-echocardiography, plasma NT-BNP levels, cardiovascular and sickle cell related symptoms and events, and quality of life scores. Recruitment into the Screening Phase and MIT was expected to extend for approximately 13 months or longer. Subjects who complete the double-blind phase were eligible to participate in the Open-label Follow-up Phase and were to be treated with sildenafil for up to 1 additional year;only AE data was collected during this period. This study was approved by the NHLBI Institutional Review Board December 26, 2007 and we began screening and enrolling subjects on December 31, 2007. At the NIH site, we screened 131 subjects: 114 subjects were enrolled in the Observational Follow-up;17 subjects were randomized into the Main Interventional Trial. Of the 17 subjects randomized, 12 completed the MIT portion of the study and 11 of these subjects continued into the open-label part of the study. On July 8, 2009 all sites were notified that based on recommendations from the DSMB all activity in the MIT and Open Label Phase of the study was to end. This recommendation was based on an unmasked report to the DSMB that described more treatment-emergent Serious Adverse Events (SAEs) in the Sildenafil group during the MIT. Then on August 13, 2009 all sites were informed that the FDA had put the entire study on Clinical Hold. On 12/10/09 the NHLBI IRB approved an amendment, which clarified that the Screening, MIT and Open-label Phases of the study had been closed, but that the Observational Follow-up portion of the study was open. The amendment study allowed for up to three years of follow-up (phone or in person) every 6 to 12 months of subjects who were initially screened for the MIT portion of the walk-PHaSST study but did not qualify or chose not to participate (some individuals chose not to participate in the MIT for various reason but agreed to return for observational follow-up) or were enrolled in the MIT portion of the walk-PHaSST study and completed/discontinued participation in the MIT/Open Label Follow-up Phase. This amendment also included a letter that was sent to the research participants informing them that the specimen repository responsibilities were transferred from SeraCare in Maryland to the University of Pittsburgh. In August 2010 we were notified by the sponsor that the study was to be closed to follow-up. During this year we completed data analysis on the primary outcome variable and on the unexpected adverse events, and the manuscript reporting these results has been published (see below). Additional secondary outcome data is under analysis, and additional manuscripts will be written and submitted.